Numerous essential biochemical reactions involve the isomerization of a substrate. Enzymes which catalyze such reactions are known as isomerases. A number of isomerases have been described catalyzing steps in a wide variety of biochemical pathways including protein folding, phototransduction, and various anabolic and catabolic pathways (e.g., glycolysis), in organisms ranging from bacteria to human.
One class of isomerases is known as peptidyl-prolyl cis-trans isomerases (PPIases). PPIases catalyze the cis to trans isomerization of certain proline imidic bonds in proteins. Two families of PPIases are the cyclophilins (CyPs), and the FK506 binding proteins (FKBPs). CyP was characterized originally as the receptor for the immunosuppressant drug cyclosporin, an inhibitor of T-cell activation. Subsequent work demonstrated that CyPs isomerase activity is essential for correct protein folding. Thus, the peptidyl-prolyl isomerase activity of CyP may be part of the signaling pathway that leads to T-cell activation. (Bergsma, D. J. et al (1991) J. Biol. Chem. 266:23204-23214.)
FKBPs bind the potent immunosuppressants FK506 and rapamycin, thereby inhibiting signaling pathways in T-cells. Specifically, the PPIase activity of FKBPs is inhibited by binding FK506 or rapamycin. There are five members of the FKBP family which are named according to their calculated molecular masses (FKBP12, FKBP13, FKBP25, FKBP52, and FKBP65), and are localized to different regions of the cell where they associate with different protein complexes. FKBP12 is localized to the cytoplasm and is associated with the ryanodine receptor and the inositol 1,4,5-trisphosphate receptor. FKBP13 is located in the endoplasmic reticulum where it's PPIase activity assists in folding growing polypeptide chains. FKBP25 is found in the nucleus and associates with nucleolin and casein kinase II. FKBP52 associates with unactivated steroid receptors. FKBP65 has been localized to the membrane, but no proteins have yet been shown to interact with it. (Coss, M. et al. (1995) J. Biol. Chem. 270:29336-29341; Schreiber, S. L. (1991) Science 251:283-287.)
Other isomerases are involved in essential biochemical reaction pathways. For example, in E. coli, 3,4-dihydroxyphenylacetate is converted to succinic semialdehyde in an aromatic catabolism pathway known as the homoprotocatechuate pathway. This pathway requires two isomerization steps. The first step is the conversion of 5-carboxymethyl-2-hydroxymuconic acid to 5-oxo-pent-3-ene-1,2,5-tricarboxylic acid by the action of 5-carboxymethyl-2-hydroxymuconate isomerase. In the second step, the enzyme 2-hydroxyhepta-2,4-diene-1,7-dioate isomerase (HHDDI) catalyzes the isomerization of 2-hydroxy-hepta-2,4-diene-1,7-dioic acid into 2-oxo-hepta-3-ene-1,7-dioic acid. These isomerization steps are essential to the breakdown of aromatic compounds which produces substrates for energy metabolism. (Roper, D. I. and Cooper, R. A. (1993) Eur. J. Biochem. 217: 575-580.)
The discovery of new human peptidyl-prolyl isomerases and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of cancer and autoimmune/inflammatory disorders.